Clinical implications of the serum platelet-to-lymphocyte ratio in the modern radiation oncology era: research update and literature review

Radiation therapy (RT) continues to be the primary approach for treating cancer, and numerous cancer biomarkers associated with oncological outcomes have been investigated in the context of RT. The serum platelet-to-lymphocyte ratio (PLR) is one of the emerging landmark biomarker in the oncologic field. Mounting evidence indicates that an elevated serum PLR may function as a marker of unfavorable tumor characteristics, adverse treatment outcomes and treatment-related toxicities among individuals undergoing RT. However, the findings of these investigations have revealed a few disparities among researchers, highlighting the need for further meticulously planned studies to draw conclusive results. This article provides a comprehensive literature review and in-depth discussion regarding the clinical implications of the serum PLR in the modern RT era.


Introduction
Radiation therapy (RT) has been the cornerstone of numerous cancer treatments [1] since the discovery of its biological efficacy against cancer cells via a variety of mechanisms [2].Moreover, the recent development of RT technologies has enabled the broad application and supply of RT equipment globally for cancer treatment [3][4][5][6][7].
There are a variety of indices and landmarks available for estimating the benefits and outcomes of RT [8][9][10][11].Blood markers are commonly and regularly tested in platelet-expressed proteins have been shown to be crucial for tumor spreading in experimental animal models, and platelets have also been implicated in the mechanisms that drive tumor angiogenesis [20][21][22][23].In addition, platelets are considered to protect circulating tumor cells (CTCs) from antitumor immune responses and thereby promote CTC metastasis [12,24].Lymphocytes, a wellknown type of blood cell, play a vital role in antitumor immune effects and inhibit tumor proliferation and migration [25].The PLR can therefore serve as one of the primary markers of cancer outcomes.
A number of studies have examined the prognostic relevance of the PLR in different types of cancer [12,19,[26][27][28][29][30].However, as multimodal approaches are commonly used in cancer treatment, the role of the PLR in the population of patients who undergo RT has not been well studied.Similarly, during our literature search for this study, we also found that most of the related studies involved patients treated with a variety of management options [31][32][33][34][35][36].The objective of this review is to summarize the PLR outcomes in different cancer cohorts of patients who underwent RT.

Summary of research investigating PLR according to cancer type
We examined the studies related to the PLR in patients with each type of cancer who underwent various therapeutic modalities including RT.The primary emphasis of the search for research articles was on RT as a treatment modality.However, the majority of cancer patients are treated using a combination of various approaches.Our aim in this review was to identify and include studies or articles from which important findings were reported and recently published.

Brain malignancies
Among brain tumors, primary radical resection is the most essential part of treatment, and studies have also included patients who underwent primary surgery and postoperative RT (PORT) in their treatment sequence.Yersal et al. [37] reported negative results for the PLR in glioblastoma patients.Treatment also varied considerably, and progression-free survival (PFS) and overall survival (OS) did not significantly differ according to the PLR.Gao et al. [38] analyzed 274 atypical meningioma patients.The preoperative PLR was significantly associated with PFS according to the receiver operating characteristic curve.The PLR, included in the risk model, was also significantly correlated with PFS in multivariate analysis.Hsu et al. [39] analyzed the results of 182 malignant glioma patients.A Post-RT PLR > 200 but not an intra-RT PLR > 200 was significantly associated with improved OS and PFS in multivariate analysis.A summary of the studies is shown in Table 1.

Breast malignancies
In an early study by Krenn-Pilko et al. [40], 793 nonmetastatic breast cancer patients were analyzed.In accordance with traditional treatment guidelines, most of the included patients underwent breast-conserving surgery and adjuvant RT.An increased preoperative PLR was significantly associated with decreased cause-specific survival (CSS) and OS in multivariate analysis.An increased PLR was significantly associated with the occurrence of distant metastases (DM) in univariate analysis.Although treatment methods and disease stages were heterogeneous because of the meta-analysis feature, a high PLR was associated with poor disease-free survival (DFS) and OS in the study by Zhang et al. [41].A greater incidence of high PLR was noted in the stage II-IV subgroup than in the stage I subgroup.In addition, the incidence of high PLR was significantly different between the lymph nodepositive and lymph node-negative groups and between the metastasis-positive and metastasis-negative groups.Although treatment types were not specified in detail, a lower PLR (≤ 210) correlated with a better DFS among patients with inflammatory breast cancer [29].The results of these studies on breast cancer are summarized in Table 2.

Gastrointestinal malignancies
The PLR has been widely studied in various gastrointestinal (GI) malignancies.Like in other studies, an increased PLR was associated with inferior outcomes in most of  3.
In esophageal cancer, pathological tumor response, DFS, PFS and OS were the main study endpoints.The pretreatment and post-treatment PLR or the change in PLR was investigated.The pretreatment PLR was significantly correlated with lymph node (LN) and distant organ metastasis according to Wang et al. [42].In contrast to most related studies, Tseng et al. [43] reported that an elevated PLR after treatment was associated with better disease-specific survival (DSS).Changes in the PLR have also shown prognostic significance in several studies [43][44][45].A greater change in the PLR was associated with inferior DFS and OS in the studies by Khin et al. [44] and Zhang et al. [45], whereas an elevated PLR after treatment was associated with better DSS in the study by Tseng et al. [43].Results indicating no correlation or statistical significance in only univariate analysis between PLR and study endpoints (OS and DFS) were also reported [46,47].Correlation between high PLR and worse pathological or clinical tumor response was also illustrated [28,48].
In hepatocellular carcinoma (HCC), the baseline PLR (pretreatment), post-treatment PLR and change in PLR were also correlated with OS and intrahepatic relapsefree survival [12,31,[49][50][51]. Lee et al. [12] reported that the highest post-treatment PLR was an independent prognostic indicator of distant control rates among patients who underwent curative intent trans-arterial chemoembolization followed by fractionated or stereotactic ablative RT.Post-treatment worsening (increase) of the PLR was significantly related to intrahepatic recurrence in Bae et al. [31].The results of other studies on HCC are described in Table 3.
In rectal cancer, both positive and negative results have been described.In positive studies, a high PLR was significantly associated with worse outcomes with decreased OS and DFS [26,52].Lateral LN recurrence was also correlated with high PLR in the study by Miyakita et al. [53].The relationship between tumor response and the PLR was also studied [54][55][56].In studies with negative results, the PLR was not associated with OS, DFS or tumor response [54,57].The opposite results were also reported in relation to other studies, in which a high PLR was associated with a better prognosis (better OS) [33].

Genitourinary and gynecological malignancies
PLR studies also demonstrated similar results as other site malignancies in genitourinary and gynecological malignancies.In a large-scale study by Langsenlehner et al. [19], high pretreatment PLR (PLR ≥ 190) was independently associated with poor metastasis-free survival (HR = 2.24), CSS (HR = 3.99), and OS (HR = 1.87) in multivariate analysis among prostate cancer patients who underwent definitive RT.However, in Huszno et al. [58], pretreatment PLR was not associated with OS among prostate cancer cohorts comprised with patients who underwent RT or surgery.Cervix cancer was vigorously studied for PLR investigation in gynecological cancer.Meta-analysis by Ma et al. [34] has shown that elevated pretreatment PLR was significantly correlated with poor major study outcomes such as OS, DFS or PFS.The PLR was also meaningfully correlated with lymphovascular invasion, LN metastasis, large tumor size (> 4 cm) and high grade (G3) tumors.The results were statistically significant although the study population was mixed.Clinical response was also another significant end-point in Chauhan et al. [59] and high pretreatment PLR significantly associated with poor response.Statistically significant and independent inferior OS or PFS was reported resulting from high pretreatment PLR in other literatures   4.

Hematological malignancies
The PLR has not been broadly studied in hematological malignancies.In Wang et al. [61], the PLR was significantly correlated with various lymphoma staging systems and a high PLR was an independent prognostic factor for inferior OS in patients with extranodal NK/T-cell lymphoma.In Hodgkin and mucosa-associated lymphoid tissue (MALT) lymphoma, a high PLR was independently linked to worse outcomes [62,63].The study results for patients with hematological malignancies are summarized in Table 5.

Head and neck malignancies
The PLR was widely investigated in various types of head and neck malignancies.Nasopharyngeal, oropharyngeal and hypopharyngeal cancers were routinely treated with definitive RT and chemotherapy as known treatment guidelines.Upfront surgery was preceded in oral and salivary gland cancers.In meta-analysis published in 2020, 3459 patients were included among 9 nasopharyngeal cancer studies [30].An increased pretreatment PLR predicted poor OS, PFS and DM free-survival (DMFS) in non-metastatic disease, whereas an increased PLR was not significantly associated with poor OS in patients with metastatic disease.A high PLR was significantly related to worse OS, PFS or DMFS in majority of the studies [30,35,[64][65][66][67].However, opposite [68] and negative results [69,70] have also been reported.In 418 patients with salivary gland cancer by Yan et al. [67], a high PLR before PORT was significantly associated with worse DMFS in multivariate analysis, and PLR-based nomogram also conveyed accurate individual predictions of DMFS.In oral squamous cell cancers, a high preoperative PLR was associated with inferior DFS or OS [65,71].The summarized results are described in Table 6.

Lung malignancies
The PLR has also been extensively investigated in small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC).In SCLC, a high PLR was associated with inferior OS or PFS in several studies [36,72,73], while no correlation was also reported [25,74].In NSCLC, a variety kind of study cohorts were enrolled in the studies.Pre-or mid-treatment PLR was correlated with OS or PFS [75,76].In early-stage NSCLC, low pretreatment PLR was significantly associated with superior non-local failure following stereotactic body radiation therapy (SBRT) [77].Delikgoz Soykut et al. [75] described interaction between the PLR and loco-regional relapse free survival.Negative results with no correlation between the PLR and clinical outcomes were also depicted [25,78].Pavan et al. [79] explored tumor immune-milieu among patients with superior sulcus NSCLC who underwent conformal RT followed by surgery.CD68 + tumor infiltrating immune cells were associated with a higher PLR and higher PLR values seemed to be linked with fewer residual viable tumor cells.However, the presurgical PLR was not associated with a radiological or metabolic response.The results are described in Table 7.

Soft tissue malignancies
The PLR was not studied well in soft tissue sarcomas.
In the study by Fiore et al. [32], 423 patients with retroperitoneal sarcoma were examined who underwent preoperative RT or RT and chemotherapy.Prognostic index comprised with initial (pretreatment) PLR significantly discriminated OS and served as an available prognostic tool in that study.Tepper et al. [80] reported treatment outcomes of 86 patients with undifferentiated pleomorphic sarcoma (UPS).All included patients underwent resection of the UPS and RT was performed via by neoadjuvant or adjuvant sequence.A high pretreatment PLR was associated with worse OS in univariate analysis but not in multivariate analysis.

Toxicities
Notably, significant correlation between the PLR and treatment toxicity has been illustrated in several studies.Among 379 esophageal cancer patients who underwent chemoradiation treatment (CRT), Han et al. [81] reported that a high pretreatment PLR was an independent predictor of esophageal fistula, and a nomogram including the PLR significantly predicted esophageal fistula.Yang et al. [82] reported that an increased PLR during 3-4 weeks of RT was the independent indicator of symptomatic radiation pneumonitis among patients with esophageal cancer who underwent RT or CRT, and PLR-based nomogram also significantly predicted symptomatic radiation pneumonitis.In contrast, an increased 6-week PLR was associated with a decreased risk of radiation pneumonitis among patients with NSCLC in Huang et al. [83].Radiation esophagitis was investigated by Qui et al. [84].A high pretreatment PLR was the significant predictor of severe esophagitis among SCLC patients.Table 8 provides a summary of studies.

Discussion
Because of the variety of cancer types, treatment modalities, and timepoints of blood tests, consistent conclusions and results could not be drawn from the review of studies.Although we sought to include, examine and analyze RT-related studies in this review, cancer types treated by RT alone are confined to several diseases only, and most of the malignancies were managed with multidisciplinary and multimodal options.Therefore, we cannot arrive at concrete and constant conclusions from these studies.Multiple blood tests are repeatedly performed even within a short period of time for chronic diseases such as cancer.Accurate quantification of the timing of blood tests seems critical, but there is a possibility of variation among studies.However, despite this heterogeneity, we can focus on several concordant conclusions and results among studies.A summary of the clinical implications of the PLR is illustrated in Fig. 1.The connection between systemic inflammation and cancer development was described in the 19th century [59].Since then, the known link between inflammation and cancer has recently undergone a renaissance as a result of investigations of the role of inflammation in cancer [59].The inflammatory microenvironment is now regarded as the seventh hallmark of cancer according to the numerous clinical and translational studies [85].Blood parameters such as platelets, leukocytes, lymphocytes, macrophages, monocytes and dendritic cells are regularly measured and compose a paramount part of the immune system.When triggered, these cells release a variety of cytokines and tumor growth-promoting factors.Platelets are among the important tumor-promoting blood cells.They release epidermal growth factor, hepatocyte growth factor, insulin-like growth factor, platelet-derived growth factor, transforming growth factor β, vascular endothelial growth factor and many cytokines that promote epithelial-to-mesenchymal transition and metastasis [86,87].Lymphocytes are also an integral part of host's cellular immunity and are involved in antitumor immune responses.Lymphocytes can induce cell death and impede the proliferation and migration of cancer cells [33].The presence of lymphocytes in the tumor is associated with improved treatment responses and favorable prognosis, whereas low lymphocyte counts are linked to diminished antitumor immune responses, which can lead to tumor growth and progression [88].
When we summarized the results, most studies illustrated association between a high PLR and poor outcomes even though consistent conclusions and trends were not found.The majority of the included studies investigated OS, DFS or PFS as primary study endpoints, and a high PLR was correlated with deteriorated outcomes at these endpoints.An association with LC has been observed in few studies, whereas a close relationship with DM has been described in several studies.Connection between a high PLR and worse clinical and pathological factors as well as disease stages have also been demonstrated.The specific relevance of the PLR in particular cancer types can be determined through well-designed studies with fixed and predefined PLR measurement timepoints.
When we examined the results according to disease site, some concordant results were observed despite the heterogeneous composition of the study groups.Among the brain tumors, atypical meningioma and malignant gliomas were included.The preoperative or Post-RT PLR was associated with PFS or OS.The PLR-including risk score also significantly correlated with PFS.In breast cancer, the PLR was  investigated from diverse perspectives.In the meta-analysis, the associations of a high PLR with advanced disease stage, LN metastasis, and DM, as well as poor DFS and OS, were reported.Interactions of the preoperative PLR with CSS and OS and a very strong association between a high PLR and DM were also depicted.In GI malignancies, the PLR has been more broadly investigated.In esophageal cancer, most included studies involved patients who underwent definitive CRT.However, studies on the heterogeneity of treatment therapeutics and studies on patients treated with neoadjuvant CRT followed by surgery were also included.Although most of the endpoints were OS, DFS or PFS, tumor response or complete response was another endpoint in some studies.
In most of those studies, elevated PLRs were associated with poor clinical outcomes and poor pathological responses.
In some studies, the PLR increased after CRT, and a high post-treatment PLR was related to poor OS.Changes in the PLR were also related to OS and DFS in several studies.The assessment timepoints of the PLR in relation to treatment time varied among studies and were linked to treatment outcomes in various aspects.LN metastasis and DM were also linked to a high PLR in some studies.The results for HCC patients were similar to those of other PLR-related studies.The highest PLR among the collected data was associated with DM, and worsening of the PLR after treatment was connected to intrahepatic recurrence.In rectal cancer, according to the standard treatment paradigm, treatment proceeded via the sequence of neoadjuvant CRT followed by radical surgery in all included studies.The results were also divided into positive (close relationship) and negative (no relationship) outcomes.An elevated PLR was related to poor OS, DFS, PFS and lateral LN recurrence.A favorable response after CRT was associated with a low PLR in some studies.In hematologic malignancies, investigations of the PLR have rarely been conducted.Extranodal NK/T-cell lymphoma, Hodgkin's lymphoma and MALT lymphoma were the disease entities studied.An increased PLR was consistently related to poor OS or PFS in all the included studies.A number of studies on head and neck malignancies have been performed for various types of cancer.In the study population of patients who underwent definitive CRT, an elevated PLR was related to poor OS, PFS or DMFS in most of the studies.Opposite or negative (no relationship) results have been reported from several studies.In the study cohorts of salivary gland cancer or oral cancer, in which upfront surgery was followed by PORT, the PLR before surgery or PORT was connected to DMFS, DFS or OS.Many investigational studies related to the PLR in lung cancer have been carried out in both SCLC and NSCLC.Similar to the finding of other studies, an elevated pretreatment PLR was related to inferior OS and PFS.The relationship with the mid-treatment PLR was also depicted.In one study, a close association with local recurrence was described.PLR-related studies of soft tissue sarcomas have rarely

Fig. 1 A
Fig. 1 A summary of the clinical implications of the increased PLR

Table 1
PLR studies in brain malignancies S-> RTPreop PLR was significantly associated with PFS (ROC analysis); PLR including risk score significantly correlated with PFS in multivariate analysis 2022 Hsu et al. [39] 182 OS, PFS Malignant gliomas S-> RT Post-RT PLR > 200 was significantly associated with improved OS and PFS in multivariate analysis PFS: Progression free survival; OS: Overall survival; S: Surgery; CRT: Chemoradiation therapy; RT: Radiation therapy; CTx: Chemotherapy; Tx: Treatment; PLR: Platelet to lymphocyte ratio; ROC: Receiver Operating Characteristic these studies.Several types of study endpoints demonstrated a close relationship with the PLR.The major results of GI malignancy studies are summarized in Table

Table 2 PLR studies in breast malignancies Year Article Total N Study end-point(s) Disease(s) Treatment(s) Important results
CSS: Cause specific survival; OS: Overall survival; DMFS: Distant metastasis free survival; BCS: Breast conserving surgery; RT: Radiation therapy; MRM: Modified radical mastectomy; PLR: Platelet to lymphocyte ratio; DFS: Disease free survival; RFS: Relapse free survival; NACT: Neoadjuvant chemotherapy; DMFS: Distant metastasis free survival nCRT-> S The median OS was significantly higher among patients with a high post-CRT PLR than among those with a low post-CRT PLR

Table 4
PLR studies in genitourinary and gynecological malignancies MFS: Metastasis free survival; CSS: Cause specific survival; OS: Overall survival; DFS: Disease free survival; RT: Radiation therapy; PLR: Platelet to lymphocyte ratio; S: Surgery; PFS: Progression free survival; CRT: Chemoradiation therapy; AUC: Area under the curve; LN: Lymph node

Table 5
PLR studies in hematological malignancies

Table 8
PLR studies related to treatment toxicities CRT: Chemoradiation therapy; PLR: Platelet to lymphocyte ratio; EF: Esophageal fistula; RT: Radiation therapy; RP: Radiation pneumonitis; OS: Overall survival; PFS: Progression free survival; NSCLC: Non-small cell lung cancer; Gr: Grade; SCLC: Small cell lung cancer; RE: Radiation esophagitis been performed.The pretreatment PLR demonstrated a close relationship with OS.Interestingly, a close connection between the PLR and treatment toxicitiy has been reported in several articles.Esophageal fistula, radiation esophagitis and radiation pneumonitis are representative examples of toxicities that have shown a close relationship with the PLR, and pretreatment or mid-treatment PLR values were significantly linked to toxicities.In summary, the PLR was associated with basic tumor characteristics, various oncologic factors, treatment outcomes and toxicities in cancer treatment involving RT.Although the results were not consistent, increased PLR mostly correlated with poor clinical features and prognosis.These features include baseline tumor characteristics; clinical study endpoints such as DFS, DM, DMFS, OS and PFS; and partly LN metastasis or local recurrence.However, some studies have shown negative or opposite results.The consistency of the PLR measurement time points in relation to the treatment and the consistency of treatment types and modalities in the study design should be paramount for drawing more accurate and firm conclusions.Future studies with results that may support more concrete and definitive conclusions are anticipated.